Scholars@Duke
Christopher Dale Kontos

Christopher Dale Kontos

Professor of Medicine
Medicine, Cardiology
cdkontos@duke.edu
Duke Box 102148, Durham, NC 27710
180A CARL Bldg, 213 Research Dr., Durham, NC 27710

Selected Publications

Is it time to reduce the length of postgraduate training for physician-scientists in internal medicine?

Journal Article JCI insight · May 2024 Physician-scientists play a crucial role in advancing medical knowledge and patient care, yet the long periods of time required to complete training may impede expansion of this workforce. We examined the relationship between postgraduate training and time ... Full text Cite

Skeletal muscle regeneration failure in ischemic-damaged limbs is associated with pro-inflammatory macrophages and premature differentiation of satellite cells.

Journal Article Genome Med · November 10, 2023 BACKGROUND: Chronic limb-threatening ischemia (CLTI), a severe manifestation of peripheral arterial disease (PAD), is associated with a 1-year limb amputation rate of approximately 15-20% and substantial mortality. A key feature of CLTI is the compromised ... Full text Link to item Cite

Structural insights into the career path between pre- and postgraduate physician-scientist training programs.

Journal Article Elife · October 2, 2023 The growing complexities of clinical medicine and biomedical research have clouded the career path for physician-scientists. In this perspective piece, we address one of the most opaque career stage transitions along the physician-scientist career path, th ... Full text Link to item Cite

Muscle progenitor cells are required for skeletal muscle regeneration and prevention of adipogenesis after limb ischemia.

Journal Article Front Cardiovasc Med · 2023 Skeletal muscle injury in peripheral artery disease (PAD) has been attributed to vascular insufficiency, however evidence has demonstrated that muscle cell responses play a role in determining outcomes in limb ischemia. Here, we demonstrate that genetic ab ... Full text Link to item Cite

Using genetically encoded fluorescent biosensors to interrogate ovarian cancer metabolism.

Journal Article J Ovarian Res · October 20, 2022 BACKGROUND: Epithelial ovarian cancer (OC) is the most lethal gynecological malignancy and patients present with significant metastatic burden, particularly to the adipose-rich microenvironment of the omentum. Recent evidence has highlighted the importance ... Full text Link to item Cite

Coupled myovascular expansion directs cardiac growth and regeneration.

Journal Article Development · September 15, 2022 Heart regeneration requires multiple cell types to enable cardiomyocyte (CM) proliferation. How these cells interact to create growth niches is unclear. Here, we profile proliferation kinetics of cardiac endothelial cells (CECs) and CMs in the neonatal mou ... Full text Link to item Cite

G6PD inhibition sensitizes ovarian cancer cells to oxidative stress in the metastatic omental microenvironment.

Journal Article Cell Rep · June 28, 2022 Ovarian cancer (OC) is the most lethal gynecological malignancy, with aggressive metastatic disease responsible for the majority of OC-related deaths. In particular, OC tumors preferentially metastasize to and proliferate rapidly in the omentum. Here, we s ... Full text Link to item Cite

Endothelial Regulation of Microvascular Growth and Stability by Ang-Tie and VEGF Signaling Pathways: A Mechanistic Computational Systems Biology Model.

Journal Article FASEB J · May 2022 The Angiopoietin-Tie (Ang-Tie) pathway is a key signaling pathway regulating vascular stability and permeability, and it significantly intersects and crosstalk with the vascular endothelial growth factor (VEGF) signaling pathway, a major signaling pathway ... Full text Link to item Cite

Pearls of wisdom for aspiring physician-scientist residency applicants and program directors.

Journal Article JCI Insight · March 22, 2022 Postgraduate physician-scientist training programs (PSTPs) enhance the experiences of physician-scientist trainees following medical school graduation. PSTPs usually span residency and fellowship training, but this varies widely by institution. Applicant c ... Full text Link to item Cite

A systems biology model of junctional localization and downstream signaling of the Ang-Tie signaling pathway.

Journal Article NPJ Syst Biol Appl · August 20, 2021 The Ang-Tie signaling pathway is an important vascular signaling pathway regulating vascular growth and stability. Dysregulation in the pathway is associated with vascular dysfunction and numerous diseases that involve abnormal vascular permeability and en ... Full text Link to item Cite

Angiopoietin-Tie Signaling Pathway in Endothelial Cells: A Computational Model.

Journal Article iScience · October 25, 2019 The angiopoietin-Tie signaling pathway is an important vascular signaling pathway involved in angiogenesis, vascular stability, and quiescence. Dysregulation in the pathway is linked to the impairments in vascular function associated with many diseases, in ... Full text Link to item Cite

Mitochondrial dysfunction in human immunodeficiency virus-1 transgenic mouse cardiac myocytes.

Journal Article J Cell Physiol · April 2019 The pathophysiology of human immunodeficiency virus (HIV)-associated cardiomyopathy remains uncertain. We used HIV-1 transgenic (Tg26) mice to explore mechanisms by which HIV-related proteins impacted on myocyte function. Compared to adult ventricular myoc ... Full text Link to item Cite

Association of Variants in BAG3 With Cardiomyopathy Outcomes in African American Individuals.

Journal Article JAMA Cardiol · October 1, 2018 IMPORTANCE: The prevalence of nonischemic dilated cardiomyopathy (DCM) is greater in individuals of African ancestry than in individuals of European ancestry. However, little is known about whether the difference in prevalence or outcomes is associated wit ... Full text Link to item Cite

Haplo-insufficiency of Bcl2-associated athanogene 3 in mice results in progressive left ventricular dysfunction, β-adrenergic insensitivity, and increased apoptosis.

Journal Article J Cell Physiol · September 2018 Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid protein that is found predominantly in the heart, skeletal muscle, and many cancers. Deletions and truncations in BAG3 that result in haplo-insufficiency have been associated with the development of d ... Full text Link to item Cite

Dysregulation of mitochondrial bioenergetics and quality control by HIV-1 Tat in cardiomyocytes.

Journal Article J Cell Physiol · February 2018 Cardiovascular disease remains a leading cause of morbidity and mortality in HIV-positive patients, even in those whose viral loads are well controlled with antiretroviral therapy. However, the underlying molecular events responsible for the development of ... Full text Link to item Cite

The Multifunctional Protein BAG3: A Novel Therapeutic Target in Cardiovascular Disease.

Journal Article JACC Basic Transl Sci · February 2018 The B-cell lymphoma 2-associated anthanogene (BAG3) protein is expressed most prominently in the heart, the skeletal muscle, and in many forms of cancer. In the heart, it serves as a co-chaperone with heat shock proteins in facilitating autophagy; binds to ... Full text Link to item Cite

BAG3 (Bcl-2-Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy.

Journal Article Circulation · July 18, 2017 BACKGROUND: Critical limb ischemia is a manifestation of peripheral artery disease that carries significant mortality and morbidity risk in humans, although its genetic determinants remain largely unknown. We previously discovered 2 overlapping quantitativ ... Full text Link to item Cite

Infection-Induced Vascular Permeability Aids Mycobacterial Growth.

Journal Article J Infect Dis · March 1, 2017 Pathogenic mycobacteria trigger formation of organized granulomas. As granulomas mature, they induce angiogenesis and vascular permeability. Here, in a striking parallel to tumor pro-angiogenic signaling, we identify angiopoietin-2 (ANG-2) induction as an ... Full text Link to item Cite

Angiopoietin-1 promotes atherosclerosis by increasing the proportion of circulating Gr1+ monocytes.

Journal Article Cardiovasc Res · January 2017 AIMS: Atherosclerosis is a chronic inflammatory disease occurring within the artery wall. A crucial step in atherogenesis is the infiltration and retention of monocytes into the subendothelial space of large arteries induced by chemokines and growth factor ... Full text Link to item Cite

Subacute limb ischemia induces skeletal muscle injury in genetically susceptible mice independent of vascular density.

Journal Article J Vasc Surg · October 2016 OBJECTIVE: The primary preclinical model of peripheral artery disease, which involves acute limb ischemia (ALI), can result in appreciable muscle injury that is attributed to the acuity of the ischemic injury. A less acute model of murine limb ischemia usi ... Full text Link to item Cite

Tie1: an orphan receptor provides context for angiopoietin-2/Tie2 signaling.

Journal Article J Clin Invest · September 1, 2016 Angiopoietin-1/Tie2 (ANG1/Tie2) signaling is well documented as regulating angiogenesis and vessel maturation. This pathway is complicated by involvement of the orphan receptor Tie1, which has been implicated as both a positive and negative regulator of AN ... Full text Link to item Cite

Methods for Acute and Subacute Murine Hindlimb Ischemia.

Journal Article J Vis Exp · June 21, 2016 Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality in developed countries, and animal models that reliably reproduce the human disease are necessary to develop new therapies for this disease. The mouse hindlimb isc ... Full text Link to item Cite

Angiopoietin-1 enhances skeletal muscle regeneration in mice.

Journal Article Am J Physiol Regul Integr Comp Physiol · April 1, 2015 Activation of muscle progenitor cell myogenesis and endothelial cell angiogenesis is critical for the recovery of skeletal muscle from injury. Angiopoietin-1 (Ang-1), a ligand of Tie-2 receptors, enhances angiogenesis and skeletal muscle satellite cell sur ... Full text Link to item Cite

Muscle cell derived angiopoietin-1 contributes to both myogenesis and angiogenesis in the ischemic environment.

Journal Article Front Physiol · 2015 Recent strategies to treat peripheral arterial disease (PAD) have focused on stem cell based therapies, which are believed to result in local secretion of vascular growth factors. Little is known, however, about the role of ischemic endogenous cells in thi ... Full text Link to item Cite

Phosphorylation of Threonine 794 on Tie1 by Rac1/PAK1 Reveals a Novel Angiogenesis Regulatory Pathway.

Journal Article PLoS One · 2015 The endothelial receptor tyrosine kinase (RTK) Tie1 was discovered over 20 years ago, yet its precise function and mode of action remain enigmatic. To shed light on Tie1's role in endothelial cell biology, we investigated a potential threonine phosphorylat ... Full text Link to item Cite

Gene Therapy for the Prevention of Vein Graft Disease

Chapter · January 1, 2015 Despite advances in the medical management of atherosclerosis, surgical revascularization using autologous veins remains a mainstay of therapy for both coronary and peripheral artery disease. However, long-term outcomes following bypass surgery are limited ... Full text Cite

Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature.

Journal Article J Clin Invest · October 2014 Retinal and choroidal neovascularization (NV) and vascular leakage contribute to visual impairment in several common ocular diseases. The angiopoietin/TIE2 (ANG/TIE2) pathway maintains vascular integrity, and negative regulators of this pathway are potenti ... Full text Link to item Cite

More than skin deep: connecting melanocyte pigmentation and angiogenic diseases.

Journal Article J Clin Invest · January 2014 Epidemiological studies have identified racial differences in susceptibility to numerous diseases, including several ocular and skin diseases characterized by increased vascular growth. In most cases, the specific mechanisms and genetic variants responsibl ... Full text Link to item Cite

Angiogenesis in peripheral artery disease: An emerging therapy targeting skeletal muscle

Journal Article · December 1, 2013 Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities causing claudication, exercise intolerance and a decreased quality of life. Despite the fact that stenosis of conduit vessels are largely responsible for PAD d ... Cite

Gene therapy for the prevention of vein graft disease.

Journal Article Transl Res · April 2013 Ischemic cardiovascular disease remains the leading cause of death worldwide. Despite advances in the medical management of atherosclerosis over the past several decades, many patients require arterial revascularization to reduce mortality and alleviate is ... Full text Link to item Cite

p53 functions in endothelial cells to prevent radiation-induced myocardial injury in mice.

Journal Article Sci Signal · July 24, 2012 Radiation therapy, which is used for the treatment of some cancers, can cause delayed heart damage. In the heart, p53 influences myocardial injury that occurs after multiple types of stress. Here, we demonstrated that p53 functioned in endothelial cells to ... Full text Link to item Cite

Skeletal muscle-specific genetic determinants contribute to the differential strain-dependent effects of hindlimb ischemia in mice.

Journal Article Am J Pathol · May 2012 Genetics plays an important role in determining peripheral arterial disease (PAD) pathology, which causes a spectrum of clinical disorders that range from clinically silent reductions in blood flow to limb-threatening ischemia. The cell-type specificity of ... Full text Link to item Cite

In vivo tumor targeting by a NGR-decorated micelle of a recombinant diblock copolypeptide.

Journal Article J Control Release · October 30, 2011 Antivascular targeting is a promising strategy for tumor therapy. This strategy has the potential to overcome many of the transport barriers associated with targeting tumor cells in solid tumors, because the tumor vasculature is directly accessible to targ ... Full text Link to item Cite

Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death.

Journal Article Free Radic Biol Med · March 1, 2011 Cadmium (Cd), a highly toxic environmental pollutant, induces neurodegenerative diseases. Recently we have demonstrated that Cd induces neuronal apoptosis in part through activation of the mammalian target of rapamycin (mTOR) pathway. However, the underlyi ... Full text Link to item Cite

VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: an in silico model.

Journal Article Am J Physiol Heart Circ Physiol · June 2010 Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis, the growth of new capillaries from existing microvasculature. In peripheral arterial disease (PAD), lower extremity muscle ischemia develops downstream of atherosclerotic obstruc ... Full text Link to item Cite

Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation.

Journal Article Cardiovasc Res · May 1, 2010 AIMS: Phosphatase and tensin homolog (PTEN) is implicated as a negative regulator of vascular smooth muscle cell (SMC) proliferation and injury-induced vascular remodelling. We tested if selective depletion of PTEN only in SMC is sufficient to promote SMC ... Full text Link to item Cite

A systems biology perspective on sVEGFR1: its biological function, pathogenic role and therapeutic use.

Journal Article J Cell Mol Med · March 2010 Angiogenesis is the growth of new capillaries from pre-existent microvasculature. A wide range of pathological conditions, from atherosclerosis to cancer, can be attributed to either excessive or deficient angiogenesis. Central to the physiological regulat ... Full text Link to item Cite

Phosphatase and tensin homologue on chromosome 10 (PTEN) directs prostaglandin E2-mediated fibroblast responses via regulation of E prostanoid 2 receptor expression.

Journal Article J Biol Chem · November 20, 2009 Prostaglandin E(2) (PGE(2)) is an arachidonic acid metabolite that counters transforming growth factor-beta-induced fibroblast activation via E prostanoid 2 (EP2) receptor binding. Phosphatase and tensin homologue on chromosome 10 (PTEN) is a lipid phospha ... Full text Link to item Cite

Angiopoietin-2 confers Atheroprotection in apoE-/- mice by inhibiting LDL oxidation via nitric oxide.

Journal Article Circ Res · June 19, 2009 Featured Publication Atherosclerosis is promoted by a combination of hypercholesterolemia and vascular inflammation. The function of Angiopoietin (Ang)-2, a key regulator of angiogenesis, in the maintenance of large vessels is unknown. A single systemic administration of Ang-2 ... Full text Link to item Cite

Computational kinetic model of VEGF trapping by soluble VEGF receptor-1: effects of transendothelial and lymphatic macromolecular transport.

Journal Article Physiol Genomics · June 10, 2009 Vascular endothelial growth factor (VEGF) signal transduction through the cell surface receptors VEGFR1 and VEGFR2 regulates angiogenesis-the growth of new capillaries from preexistent microvasculature. Soluble VEGF receptor-1 (sVEGFR1), a nonsignaling tru ... Full text Link to item Cite

Endogenous S-nitrosothiols protect against myocardial injury.

Journal Article Proc Natl Acad Sci U S A · April 14, 2009 Despite substantial evidence that nitric oxide (NO) and/or endogenous S-nitrosothiols (SNOs) exert protective effects in a variety of cardiovascular diseases, the molecular details are largely unknown. Here we show that following left coronary artery ligat ... Full text Link to item Cite

Phosphatase and tensin homolog (PTEN) regulates hepatic lipogenesis, microsomal triglyceride transfer protein, and the secretion of apolipoprotein B-containing lipoproteins.

Journal Article Hepatology · December 2008 Hepatic apolipoprotein B (apoB) lipoprotein production is metabolically regulated via the phosphoinositide 3-kinase cascade; however, the role of the key negative regulator of this pathway, the tumor suppressor phosphatase with tensin homology (PTEN), is u ... Full text Link to item Cite

Up-regulating sphingosine 1-phosphate receptor-2 signaling impairs chemotactic, wound-healing, and morphogenetic responses in senescent endothelial cells.

Journal Article J Biol Chem · October 31, 2008 Vascular endothelial cells (ECs) have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest state called "cellular senescence." It has been shown that sphingolipids may be involved in senescence; however, the molecular ... Full text Link to item Cite

A VEGF trap inhibits the beneficial effect of bFGF on vasoreactivity in corporal tissues of hypercholesterolemic rabbits.

Journal Article J Sex Med · September 2008 Featured Publication INTRODUCTION: Hypercholesterolemia causes a decrease in normal corporal tissue vasoreactivity in a preclinical model of erectile dysfunction. Previous studies have shown that intracorporal injection (ICI) of basic fibroblast growth factor (bFGF) reverses s ... Full text Link to item Cite

Plasma levels of soluble Tie2 and vascular endothelial growth factor distinguish critical limb ischemia from intermittent claudication in patients with peripheral arterial disease.

Journal Article J Am Coll Cardiol · July 29, 2008 Featured Publication OBJECTIVES: Our purpose was to determine whether factors that regulate angiogenesis are altered in peripheral arterial disease (PAD) and whether these factors are associated with the severity of PAD. BACKGROUND: Alterations in angiogenic growth factors occ ... Full text Link to item Cite

High cholesterol feeding in C57/Blc6 mice alters expression within the VEGF receptor-ligand family in corporal tissue.

Journal Article J Sex Med · May 2008 INTRODUCTION: Angiogenesis, the growth and proliferation of blood vessels from existing vascular structures, is mediated by many cytokine growth factors and receptors, among the most important are the vascular endothelial growth factor (VEGF) family. AIM: ... Full text Link to item Cite

Inhibition of in vivo tumor angiogenesis and growth via systemic delivery of an angiopoietin 2-specific RNA aptamer.

Journal Article J Surg Res · May 1, 2008 BACKGROUND: Cellular events mediated by the Tie2 receptor are important to tumor neovascularization. Despite the complex interplay of the best-characterized Tie2 ligands, angiopoietins 1 and 2, Ang2 is purportedly "proangiogenic" in the presence of vascula ... Full text Link to item Cite

RNA Aptamer-targeted Inhibition of NF-κB Suppresses Non-small Cell Lung Cancer Resistance to Doxorubicin.

Journal Article Mol Ther · January 2008 Due to the prevalence of tumor chemoresistance, the clinical response of advanced non-small cell lung cancer (NSCLC) to chemotherapy is poor. We suppressed tumor resistance to doxorubicin (Dox) in A549 cells, a human NSCLC cell line, both in vitro and in v ... Full text Link to item Cite

A nuclease-resistant RNA aptamer specifically inhibits angiopoietin-1-mediated Tie2 activation and function.

Journal Article Angiogenesis · 2008 Featured Publication Tie2 is a receptor tyrosine kinase that is expressed predominantly in the endothelium and plays key roles in both physiological and pathological angiogenesis. The ligands for Tie2, the angiopoietins (Ang), perform opposing functions in vascular maintenance ... Full text Link to item Cite

VEGF induces Tie2 shedding via a phosphoinositide 3-kinase/Akt dependent pathway to modulate Tie2 signaling.

Journal Article Arterioscler Thromb Vasc Biol · December 2007 Featured Publication OBJECTIVE: Tie2 and its ligands, the angiopoietins (Ang), are required for embryonic and postnatal angiogenesis. Previous studies have demonstrated that Tie2 is proteolytically cleaved, resulting in the production of a 75-kDa soluble receptor fragment (sTi ... Full text Link to item Cite

Impaired angiogenesis after hindlimb ischemia in type 2 diabetes mellitus: differential regulation of vascular endothelial growth factor receptor 1 and soluble vascular endothelial growth factor receptor 1.

Journal Article Circ Res · October 26, 2007 Featured Publication Deficient angiogenesis after ischemia may contribute to worse outcomes of peripheral arterial disease in patients with diabetes mellitus (DM). Vascular endothelial growth factor (VEGF) and its receptors promote angiogenesis. We hypothesized that in periphe ... Full text Link to item Cite

Systemic overexpression of angiopoietin-2 promotes tumor microvessel regression and inhibits angiogenesis and tumor growth.

Journal Article Cancer Res · April 15, 2007 Angiopoietin-2 (Ang-2) is a conditional antagonist and agonist for the endothelium-specific Tie-2 receptor. Although endogenous Ang-2 cooperates with vascular endothelial growth factor (VEGF) to protect tumor endothelial cells, the effect on tumor vasculat ... Full text Link to item Cite

Engineered transcription factors for therapeutic angiogenesis.

Journal Article Curr Opin Mol Ther · April 2007 Featured Publication Angiogenesis is defined as the growth and proliferation of blood vessels from existing vascular structures. Therapeutic angiogenesis seeks to harness the mechanisms of vascular growth to treat disorders of inadequate tissue perfusion. Early clinical trials ... Link to item Cite

In mice with type 2 diabetes, a vascular endothelial growth factor (VEGF)-activating transcription factor modulates VEGF signaling and induces therapeutic angiogenesis after hindlimb ischemia.

Journal Article Diabetes · March 2007 Featured Publication Peripheral arterial disease is a major complication of diabetes. The ability to promote therapeutic angiogenesis may be limited in diabetes. Type 2 diabetes was induced by high-fat feeding C57BL/6 mice (n = 60). Normal chow-fed mice (n = 20) had no diabete ... Full text Link to item Cite

APOE4-VLDL inhibits the HDL-activated phosphatidylinositol 3-kinase/Akt Pathway via the phosphoinositol phosphatase SHIP2.

Journal Article Circ Res · October 13, 2006 Endothelial cell dysfunction and apoptosis are critical in the pathogenesis of atherosclerotic cardiovascular disease (CVD). Both endothelial cell apoptosis and atherosclerosis are reduced by high-density lipoprotein (HDL). Low HDL levels increase the risk ... Full text Link to item Cite

An engineered vascular endothelial growth factor-activating transcription factor induces therapeutic angiogenesis in ApoE knockout mice with hindlimb ischemia.

Journal Article J Vasc Surg · July 2006 Featured Publication OBJECTIVE: Angiogenesis is the growth and proliferation of blood vessels from existing vascular structures, and therapeutic angiogenesis seeks to promote blood vessel growth to improve tissue perfusion. Vascular endothelial growth factor (VEGF) is a protot ... Full text Link to item Cite

Efficacy and mechanism of adenovirus-mediated VEGF-165 gene therapy for augmentation of skin flap viability.

Journal Article Am J Physiol Heart Circ Physiol · July 2006 Skin ischemic necrosis due to vasospasm and/or insufficient vascularity is the most common complication in the distal portion of the skin flap in reconstructive surgery. This project was designed to test our hypothesis that preoperative subdermal injection ... Full text Link to item Cite

A comparison of antiangiogenic therapies for the prevention of liver metastases.

Journal Article J Surg Res · March 2006 Angiogenesis is essential for solid tumor growth. Although successful antiangiogenic therapies have been demonstrated in animal models, a systematic comparison of the efficacy of different antiangiogenic factors has not been described in the hepatic enviro ... Full text Link to item Cite

Negative regulation of myofibroblast differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on chromosome 10).

Journal Article Am J Respir Crit Care Med · January 1, 2006 Featured Publication RATIONALE: Myofibroblasts are primary effector cells in idiopathic pulmonary fibrosis (IPF). Defining mechanisms of myofibroblast differentiation may be critical to the development of novel therapeutic agents. OBJECTIVE: To show that myofibroblast differen ... Full text Link to item Cite

H1 RNA polymerase III promoter-driven expression of an RNA aptamer leads to high-level inhibition of intracellular protein activity.

Journal Article Nucleic Acids Res · 2006 Aptamers offer advantages over other oligonucleotide-based approaches that artificially interfere with target gene function due to their ability to bind protein products of these genes with high affinity and specificity. However, RNA aptamers are limited i ... Full text Link to item Cite

Loss of phosphatase and tensin homologue increases transforming growth factor beta-mediated invasion with enhanced SMAD3 transcriptional activity.

Journal Article Cancer Res · December 15, 2005 In normal epithelial tissues, the multifunctional cytokine transforming growth factor-beta (TGF-beta) acts as a tumor suppressor through growth inhibition and induction of differentiation whereas in advanced cancers, TGF-beta promotes tumor progression thr ... Full text Link to item Cite

Cholesterol feeding reduces vascular endothelial growth factor signaling in rabbit corporal tissues.

Journal Article J Sex Med · September 2005 PURPOSE: Hypercholesterolemia is a major risk factor for erectile dysfunction (ED), but the mechanisms are not completely understood. Vascular endothelial growth factor (VEGF) is reduced in rabbit corporal tissue with cholesterol feeding. VEGF signaling le ... Full text Link to item Cite

A crucial role for GRK2 in regulation of endothelial cell nitric oxide synthase function in portal hypertension.

Journal Article Nat Med · September 2005 Featured Publication Nitric oxide (NO) production by endothelial cell nitric oxide synthase (eNOS) in sinusoidal endothelial cells is reduced in the injured liver and leads to intrahepatic portal hypertension. We sought to understand the mechanism underlying defective eNOS fun ... Full text Link to item Cite

Systemic soluble Tie2 expression inhibits and regresses corneal neovascularization.

Journal Article Biochem Biophys Res Commun · June 24, 2005 This study was designed to determine if soluble Tie2 (sTie2) expression inhibits and regresses corneal neovascularization, and if VEGF contributes to its effect. The corneas of BALB/c mice were scraped and the mice were injected with either an adenovirus e ... Full text Link to item Cite

Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts.

Journal Article J Thorac Cardiovasc Surg · June 2005 Featured Publication OBJECTIVES: Fifty percent of human aortocoronary saphenous vein grafts are occluded after 10 years. Intimal hyperplasia is an initial step in graft occlusion and consists of vascular smooth muscle cell proliferation. Phosphatidylinositol 3-kinase and its d ... Full text Link to item Cite

PTEN as an effector in the signaling of antimigratory G protein-coupled receptor.

Journal Article Proc Natl Acad Sci U S A · March 22, 2005 PTEN, a tumor suppressor phosphatase, is important in the regulation of cell migration and invasion. Physiological regulation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) by cell surface receptors has not been described. Here, we show ... Full text Link to item Cite

Adenovirus-mediated intraarterial delivery of PTEN inhibits neointimal hyperplasia.

Journal Article Arterioscler Thromb Vasc Biol · February 2005 Featured Publication OBJECTIVE: Phosphoinositide (PI) 3-kinase promotes vascular smooth muscle cell (VSMC) responses necessary for neointimal hyperplasia. We recently demonstrated that the inositol 3-phosphatase PTEN is expressed in VSMCs and that its overexpression inhibits t ... Full text Link to item Cite

Angiogenesis and angiogenic growth factors as future therapies for cerebrovascular disease

Chapter · January 1, 2005 Angiogenesis is defined as the growth and proliferation of blood vessels from existing vascular structures (1, 2). Since blood vessels sub-serve the critical biological function of delivering oxygen and removing toxins from target organs, this part of the ... Full text Cite

Acute local subcutaneous VEGF165 injection for augmentation of skin flap viability: efficacy and mechanism.

Journal Article Am J Physiol Regul Integr Comp Physiol · November 2004 Distal skin ischemic necrosis is a common complication in skin flap surgery. The pathogenesis of skin flap ischemic necrosis is unclear, and there is no clinical treatment available. Here, we used the 4 x 10 cm rat dorsal skin flap model to test our hypoth ... Full text Link to item Cite

Engineered zinc finger-activating vascular endothelial growth factor transcription factor plasmid DNA induces therapeutic angiogenesis in rabbits with hindlimb ischemia.

Journal Article Circulation · October 19, 2004 Featured Publication BACKGROUND: Therapeutic angiogenesis seeks to promote blood vessel growth to improve tissue perfusion. Vascular endothelial growth factor (VEGF) exists in multiple isoforms. We investigated an engineered zinc finger-containing transcription factor plasmid ... Full text Link to item Cite

IQGAP1, a novel vascular endothelial growth factor receptor binding protein, is involved in reactive oxygen species--dependent endothelial migration and proliferation.

Journal Article Circ Res · August 6, 2004 Endothelial cell (EC) proliferation and migration are important for reendothelialization and angiogenesis. We have demonstrated that reactive oxygen species (ROS) derived from the small GTPase Rac1-dependent NAD(P)H oxidase are involved in vascular endothe ... Full text Link to item Cite

Targeting the Tie2/Tek receptor in astrocytomas.

Journal Article Am J Pathol · February 2004 Tie2 is an endothelial cell-specific receptor tyrosine kinase, whose activation is positively and negatively modulated by angiopoietin-1 and angiopoietin-2, respectively. Angiopoietin-mediated modulation of Tie2 activation contributes to normal vessel deve ... Full text Link to item Cite

Responses of vascular endothelial cells to angiogenic signaling are important for tumor cell survival.

Journal Article FASEB J · February 2004 Neoplastic cells overexpress several angiogenic cytokines, which stimulate neovascularization. Whether the responses of the host endothelial cells to these signaling molecules affect tumor cells during early tumorigenesis has not been investigated. We inve ... Full text Link to item Cite

Functional significance of Tie2 signaling in the adult vasculature.

Journal Article Recent Prog Horm Res · 2004 Featured Publication Abundant data now demonstrate that the growth of new blood vessels, termed angiogenesis, plays both pathological and beneficial roles in human disease. Based on these data, a tremendous effort has been undertaken to understand the molecular mechanisms that ... Full text Link to item Cite

Endothelin-1 activates endothelial cell nitric-oxide synthase via heterotrimeric G-protein betagamma subunit signaling to protein jinase B/Akt.

Journal Article J Biol Chem · December 12, 2003 Endothelin-1 has dual vasoactive effects, mediating vasoconstriction via ETA receptor activation of vascular smooth muscle cells and vasorelaxation via ETB receptor activation of endothelial cells. Although it is commonly accepted that endothelin-1 binding ... Full text Link to item Cite

Activation of vascular endothelial growth factor receptor-1 sustains angiogenesis and Bcl-2 expression via the phosphatidylinositol 3-kinase pathway in endothelial cells.

Journal Article Diabetes · December 2003 Vascular insufficiency and retinal ischemia precede many proliferative retinopathies and stimulate secretion of various vasoactive growth factors, including vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF). It is unclear, however ... Full text Link to item Cite

Inhibition of rat corneal angiogenesis by a nuclease-resistant RNA aptamer specific for angiopoietin-2.

Journal Article Proc Natl Acad Sci U S A · April 29, 2003 Featured Publication Angiopoietin-2 (Ang2) appears to be a naturally occurring antagonist of the endothelial receptor tyrosine kinase Tie2, an important regulator of vascular stability. Destabilization of the endothelium by Ang2 is believed to potentiate the actions of proangi ... Full text Link to item Cite

Deletion of the carboxyl terminus of Tie2 enhances kinase activity, signaling, and function. Evidence for an autoinhibitory mechanism.

Journal Article J Biol Chem · August 30, 2002 Featured Publication Tie2 is an endothelial receptor tyrosine kinase that is required for both embryonic vascular development and tumor angiogenesis. There is considerable interest in understanding the mechanisms of Tie2 activation for therapeutic purposes. The recent solution ... Full text Link to item Cite

Inhibition of vascular smooth muscle cell proliferation, migration, and survival by the tumor suppressor protein PTEN.

Journal Article Arterioscler Thromb Vasc Biol · May 1, 2002 Phosphatidylinositol (PI) 3-kinase signaling regulates numerous cellular processes, including proliferation, migration, and survival, which are required for neointimal hyperplasia and restenosis. The effectors of PI 3-kinase are activated by the phospholip ... Full text Link to item Cite

PTEN modulates vascular endothelial growth factor-mediated signaling and angiogenic effects.

Journal Article J Biol Chem · March 29, 2002 Featured Publication Phosphatidylinositol 3-kinase is activated by vascular endothelial growth factor (VEGF), and many of the angiogenic cellular responses of VEGF are regulated by the lipid products of phosphatidylinositol 3-kinase. The tumor suppressor PTEN has been shown to ... Full text Link to item Cite

The endothelial receptor tyrosine kinase Tie1 activates phosphatidylinositol 3-kinase and Akt to inhibit apoptosis.

Journal Article Mol Cell Biol · March 2002 Featured Publication Tie1 is an orphan receptor tyrosine kinase that is expressed almost exclusively in endothelial cells and that is required for normal embryonic vascular development. Genetic studies suggest that Tie1 promotes endothelial cell survival, but other studies hav ... Full text Link to item Cite

Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide.

Journal Article Am J Pathol · September 2001 The known responses of vascular endothelial growth factor (VEGF) are mediated through VEGF receptor-2 (VEGFR-2/KDR) in endothelial cells. However, it is unknown whether VEGFR-1 (Flt-1) is an inert decoy or a signaling receptor for VEGF during physiological ... Full text Link to item Cite

HCPTPA, a protein tyrosine phosphatase that regulates vascular endothelial growth factor receptor-mediated signal transduction and biological activity.

Journal Article J Biol Chem · December 31, 1999 Angiogenesis is a tightly controlled process in which signaling by the receptors for vascular endothelial growth factor (VEGF) plays a key role. In order to define signaling pathways downstream of VEGF receptors (VEGFR), the kinase domain of VEGFR2 (Flk-1) ... Full text Link to item Cite

Angiogenesis.

Journal Article Curr Atheroscler Rep · September 1999 Angiogenesis, the growth and proliferation of blood vessels from existing vascular structures, is tightly regulated in adult tissues, and abnormalities in angiogenesis are associated with a number of pathologic states. Strategies designed to promote angiog ... Full text Link to item Cite

Allelic and locus heterogeneity in inherited venous malformations.

Journal Article Hum Mol Genet · July 1999 Venous malformations are low-flow vascular lesions consisting of disorganized thin-walled vascular channels. These can occur sporadically but also as an autosomal dominant condition termed venous malformations, cutaneous and mucosal (VMCM; OMIM 600195). In ... Full text Link to item Cite

Tyrosine 1101 of Tie2 is the major site of association of p85 and is required for activation of phosphatidylinositol 3-kinase and Akt.

Journal Article Mol Cell Biol · July 1998 Featured Publication Tie2 is an endothelium-specific receptor tyrosine kinase that is required for both normal embryonic vascular development and tumor angiogenesis and is thought to play a role in vascular maintenance. However, the signaling pathways responsible for the funct ... Full text Link to item Cite

Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis.

Journal Article Br J Cancer · 1998 Endothelial receptor tyrosine kinases may play important roles in pathological vascular growth, particularly in tumours. In this study, immunohistochemistry was used to evaluate the expression of a novel endothelial receptor tyrosine kinase, Tie2/Tek, in t ... Full text Link to item Cite

Cytochemical detection of superoxide in cerebral inflammation and ischemia in vivo.

Journal Article Am J Physiol · October 1992 We used a cytochemical technique for the detection of superoxide in cerebral inflammation and ischemia-reperfusion in anesthetized cats. The technique is based on the oxidation of Mn2+ to Mn3+ by superoxide; Mn3+, in turn, oxidizes diaminobenzidine. The ox ... Full text Link to item Cite